title: 7b, a novel naphthalimide derivative, exhibited anti-inflammatory effects via targeted-inhibiting TAK1 following down-regulation of ERK1/2- and p38 MAPK-mediated activation of NF-κB in LPS-stimulated RAW264.7 macrophages.
abstract: Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers. 7b, a novel naphthalimide-based DNA intercalator, has exhibited anti-inflammatory effects in phorbol12-myristate 13-acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells in our previous study. Here, we tried to further investigate its anti-inflammatory potential and the possible underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and primary mouse macrophages. In our current study, ELISA and Real-time PCR revealed that non-toxic doses of 7b reduced the production and expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells and primary mouse macrophages. Moreover, 7b dose-dependently suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO). Except for COX-1, non-toxic doses of 7b exhibited parallel inhibition of LPS-induced expression of COX-2 and iNOS at both mRNA and protein levels. The molecular mechanism was associated with inhibition of the phosphorylation/degradation of IκB-α and nuclear translocation of the NF-κB p65. Further analysis of upstream mechanisms showed that blocking of NF-κB activation by 7b was mediated by inhibiting TAK1-downstream extracellular signal-regulated kinase (ERK1/2) and p38 kinase signal pathway. Taken together, these results indicated that 7b exhibited anti-inflammatory effects by targeting inhibiting TAK1, leading to ERK1/2- and p38 MAPK-mediated inactivation of NF-κB in LPS-stimulated RAW264.7 cells, and this would make 7b a strong candidate for further study as anti-inflammatory agent.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Shao
authors.forename: Yiquan
authors.initials: Y
authors.lastname: Li
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Xiao
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Lu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D053644:Naphthalimides / Q000138:chemical synthesis / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053644:Naphthalimides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010879:Piperazines; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C558824:6-(dodecylamino)-2-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo-(de)isoquinoline-1,3(2H)-dione
keywords: 7b; Anti-inflammatory; MAPK; NF-κB; TAK1